The multifaceted capability of neocortex emerges from its complicated cellular constituents, particularly the exceptionally diverse interneurons operating in an intricately organized circuit. Over the years many researchers have used primarily dual or triple whole-cell recordings to examine one or two, often ambiguously identified interneurons in incomplete circuits. As a consequence, most researchers have been overwhelmed by the differences between their results, much like the tale of "three blind men and an elephant," and have come to believe that the cortex consists of at least a few dozen of distinct types of interneurons and these interneurons must thus form a sophisticated cortical inhibitory network. In this application, we plan to develop a stable simultaneous octuple whole-cell recording technology to directly record and compare multiple anatomically identified interneurons in complete cortical inhibitory circuits (to see a more complete picture of the elephant). Based on our preliminary data, we propose to test whether cortical interneurons may be classified into a handful of groups based on their axonal arborization, and whether these interneurons serve functionally different roles in column- (aim 1), laminar- (aim 2) and/or subcellular domain (aim 3)-specific circuits. Our central hypothesis is that the cortical interneuronal network is constituted by nine general types of interneurons and is organized following three elemental rules. The findings from this project will support these surprisingly simple cortical interneuron classification scheme and circuit organizational principles. Because altered interneuronal function is a common mechanism contributing to various neurological disorders, including autisms, epilepsy, depression, Huntington's disease, neurofibromatosis, schizophrenia, Tourette's syndrome and trauma, this project will also help to build the groundwork for future identification of specific interneuron type(s) and/or circuit(s) altered in each of these neurological diseases. PUBLIC HEALTH RELEVANCE: The complex capability of neocortex emerges from its complicated cellular constituents, particularly the exceptionally diverse interneurons operating in an intricately organized circuit. Here, we propose to develop a stable simultaneous octuple whole-cell recording technology to investigate multiple anatomically distinct interneurons in complete cortical inhibitory circuits. The findings should validate the axonal arborization-based cortical interneuron classification scheme, unveil the circuit organizational rules, and help to build the groundwork for future identification of specific interneuron type(s) and/or circuit(s) altered in a number of neurological diseases.